Blood Pressure-Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of cGMP-Dependent Protein Kinase

Background: The health-promoting and disease-limiting abilities of resveratrol, a natural polyphenol, has led to considerable interest in understanding the mechanisms of its therapeutic actions. The polyphenolic rings of resveratrol enable it to react with and detoxify otherwise injurious oxidants. Whilst the protective actions of resveratrol are commonly ascribed to its antioxidant activity, here we show that this is a misconception. Methods: The ability of resveratrol to oxidize cGMP-dependent PKG1 alpha (protein kinase 1 alpha) was assessed in isolated rat aortic smooth muscle cells, and the mechanism of action of this polyphenol was characterized using in vitro experiments, mass spectrometry and electron paramagnetic resonance. The blood pressure of wild-type and C42S knock-in mice was assessed using implanted telemetry probes. Mice were made hypertensive by administration of angiotensin II via osmotic mini-pumps and blood pressure monitored during 15 days of feeding with chow diet containing vehicle or resveratrol. Results: Oxidation of the phenolic rings of resveratrol paradoxically leads to oxidative modification of proteins, explained by formation of a reactive quinone that oxidizes the thiolate side chain of cysteine residues; events that were enhanced in cells under oxidative stress. Consistent with these observations and its ability to induce vasodilation, resveratrol induced oxidative activation of PKG1 alpha and lowered blood pressure in hypertensive wild-type mice, but not C42S PKG1 alpha knock-in mice that are resistant to disulfide activation. Conclusions: Resveratrol mediates lowering of blood pressure by paradoxically inducing protein oxidation, especially during times of oxidative stress, a mechanism that may be a common feature of antioxidant molecules.